There is considerable evidence that noxious stimulation produces N-methyl- D-aspartate (NMDA)-mediated long-term changes in the physiology and chemistry of dorsal horn neurons. Our laboratory has provided new evidence that links the neurotransmitter Substance P(SP) to these changes. We have demonstrated rapid internalization of the substance P receptor (SPR) in subpopulations of spinal cord neurons in response to stimulation with SP. There is also a dramatic and reversible structural reorganization of the dendrites of neurons that express the SPR. The dendrites become highly varicose and the diameter of the dendrites between varicosities is significantly reduced, compared to normal. We have also demonstrated that intrathecal injection of NMDA or noxious stimulation of the hindpaw evokes these changes. This suggests that these changes are a normal response to SP-mediated inputs. Our proposed studies will further characterize the neurons that undergo these changes and will address the opioid regulation of these changes. In related study we will use antisera directed against the recently cloned opioid receptors to determine the relationship of neurons that express the SPR with those that express the opioid receptors. We hypothesize that the structural changes of neurons that express the SPR constitute a significant component of the noxious stimulus-evoked short and long-term changes in spinal cord neurons, and suggest that NMDA-mediated hyperalgesic states result at least in part from release of SP from primary afferent fibers. We will test these hypotheses using anatomical, neurochemical, physiological and pharmacological approaches. We will also test the hypothesis that changes in the process of SPR internalization contribute to the differences that characterize nociceptive and neuropathic pain models, which are respectively associated with chronic up and downregulation of SP levels in the dorsal horn. Taken together these studies will provide important new information on the pathophysiology and the clinical consequences of injury-evoked long-term changes in the spinal cord dorsal horn.